1-amino-pyridinium salts



llnited States Latent O ce Cl. 260294.8 3 Claims ABSTRACT OF THEDISCLOSURE Pyridine salts of the formula A wherein R is phenyl or phenylsubstituted by at least one halogen, alkyl, hydroxy, or alkoxy and X isa pharmaceutically acceptable anion, are produced by reacting a pyridineof the formula wherein R is as defined above, with an aminating agent,and recovering the pyridinium salt produced. These compounds exhibitantihypertensive activity.

This application is a divisional of our copending application Ser. No.587,430 filed Nov. 18, 1966, now Pat. No. 3,466,295 granted on Sept. 9,1969.

.This invention relates to novel heterocyclic compounds havingbiological activity.

The present invention provides pyridinium salts of the general formula Ll N:

(where R has the meaning given above). For example, compounds of FormulaII may be directly aminated with chloramine or withhydroxylamine-O-sulphonic acid or 3,549,649 Patented Dec. 22, 1970 theymay be reacted with an arylsulphonyl azide to give aN-arylsulphonamido-pyridine of the general formula (where R has themeaning given above and Ar is an aryl radical) which may be convertedinto the desired compound by acid hydrolysis.

In an alternative method of preparing compounds of the general Formula Iin which R is in the 4-position of the pyridine nucleus aN-nitrosopiperidine derivative of the general formula (where R has themeaning given above) is reacted with an acylating agent, such as amixture of acetic anhydride and acetic acid, to give a pyridinederivative of the general formula (where R has the meaning given aboveand Ac is an acyl, preferably acetyl, group) and the pyridine derivativeof the general Formula V is then subjected to acid hydrolysis.

The compounds of the present invention are normally isolated from thereaction mixtures as the halides, especially the chlorides or iodides,and these salts may be converted into other desired salts byconventional techniques such as metathesis.

The compounds of the present invention have been found to have usefulpharmacological activity and more particularly they exhibit anantihypertensive activity.

The compounds may be employed in the usual forms for thorapeuticadministration. For example, they may be formulated with apharmaceutical carrier to provide tablets, capsules, suppositories,injection solutions and the like.

The daily dose of the active ingredient is in the range of 5 to 500 mg.depending on the age, weight, and condition of the patient.

The following examples illustrate the invention.

EXAMPLE 1 Preparation of 1-amino-4-pheny1pyridinium iodide 9.1 g. of4-phenylpyridine was added slowly to a solution of 2.8 g. ofhydroxylamine-O-sulphonic acid in 16 ml. of water. The mixture washeated on a steam bath for 20 minutes and then, after cooling, it wasbasified and the resultant green mixture was distilled to dryness underreduced pressure, keeping the temperature below 40 C. The residue wasdissolved in 30 ml. of ethanol and the solution was filtered. Thefiltrate was acidified with 4 ml. of hydriodic acid (s.g. 1.94) and wasthen cooled to -20 C. The resulting solid was removed by filtration andcrystallised from a mixture of 25 ml. of ethanol and 5 ml. of isopropylacetate to give a dark brown solid,

M.P. 166 C., which was recrystallised to give l-amino-4-phenylpyridinium iodide, M.P. 171 C.

EXAMPLE 2 Preparation of 1-amino-4-phenylpyridinium chloride 103 g. of1-nitroso-4-phenyl-4-piperidinol, 200 ml. of acetic anhydride and 200ml. of acetic acid were heated under reflux for 18 hours. Some brownfumes were evolved and the solution turned dark red. After cooling, thereaction mixture was slowly poured into litres of water.

A solid crystallised out and was removed by filtration. The aqueousfiltrate was basified with 43% W./V. sodium hydroxide solution andextracted with four 1 litre portions of chloroform. The combinedchloroform extracts were extracted twice with 500 ml. of 0.2 Nhydrochloric acid. The acid extracts were basified with 43% w./v. sodiumhydroxide and extracted with three 300 ml. portions of chloroform. Thedark green chloroform extracts were washed with a small quantity ofwater, dried over sodium sulphate and the solvent removed. The residuewas twice recrystallised from a mixture of 100 ml. of chloroform and 100ml. of benzene to give l-acetamido- 4-phenylpyridine, M.P. 225 to 226C., of the structure.

(lls s I 'N-CO CH;

7.4 g. of l-acetamido-4-phenylpyridine was dissolved in 250 ml. ofmethanol saturated with hydrogen chloride and the solution was heatedunder reflux for 4 hours. The methanol was removed and the residuerecrystallised from a mixture of 50 ml. of ethanol and 35 ml. ofisopropyl acetate to give 1-amino-4-phenylpyridinium chloride as a creamsolid, M.P. 210 C.

1-amino-4-phenylpyridinium chloride was converted into the iodide by thefollowing method:

A small quantity of l-amino-4-phenylpyridinium chloride was heated Withacetone and sufl'icient ethanol to effect solution. A hot acetonesolution of sodium iodide was added and the clear solution allowed tocool. The precipitated sodium chloride was removed by filtration and thesolution was evaporated to dryness. The residue Was recrystallised fromethanol to give l-amino-4-phenylpyridinium iodide, M.P. 171 C.

EXAMPLE 3 Preparation of 1-amino-4-(p-tolyl) pyridinium chloride 1.2 g.of hydroxylamine-O-sulphonic acid was dissolved in 5 ml. of water, 3.5g. of 4-(p-tolyl) pyridine was added, and the mixture heated at 85 to 90C. for one hour. The water was removed by heating on the steam bathunder reduced pressure and the residue heated under a reflux with ml. ofacetic anhydride for one hour. The excess anhydride was removed bydistillation under reduced pressure and the residue was dissolved inWater. Benzene was added and the mixture basified by the addition ofsolid sodium carbonate. The mixture was filtered and the solid washedwith water and benzene. The filtrate was separated and the aqueous layerextracted once with benzene. The aqueous layer was then extracted threetimes with chloroform and the filtered solid was dissolved in thecombined chloroform extracts. The solvent was removed and the residuerecrystallised from a mixture of chloroform and benzene. Thecrystallised material was dissolved in ml. of methanol saturated withhydrogen chloride and the solution was heated under reflux for twohours. The methanol was removed and the residue recrystallised fromethanol to give l-amino- 4-(p-tolyl) pyridinium chloride as a brown.SOlid, M.P- 34 C.

4 EXAMPLE 4 Preparation of 1-amino-4-(4-chlorophenyl) pyridiniumchloride 3.4 g. of hydroxylamine O-sulphonic acid was dissolved in 25ml. of Water, 11.4 g. of 4-(4-chlorophenyl) pyridine was added, and themixture heated at 8590 C. for one hour. The water was removed by heatingon the steam bath under reduced pressure and the residue heated underreflux with 20 ml. of acetic anhydride for one hour. The excessanhydride was removed by distillation under reduced pressure and theresidue was dissolved in water. Benzene was added and the mixturebasified by the addition of solid potassium carbonate. The mixture wasfiltered and the solid washed with water and benzene. The solid wasdissolved in 100 ml. of hot chloroform, treated with charcoal, filtered,and reduced in volume to ml. The solid obtained on cooling the abovesolution was filtered, dried, dissolved in 25 ml. of ethanol saturatedwith hydrogen chloride and the solution was heated under reflux for onehour. The ethanol was removed and the residue recrystallised from amixture of methanol and isopropanol to give l-amino-4-(4-chlorophenyl)pyridinium chloride as an off-white solid, M.P. 2223 C.

EXAMPLE 5 Preparation of 1-amino-4-(3,4-dimethoxyphenyl) pyridiniumchloride 3.0 g. of hydroxylamine-O-sulphonic acid was dissolved in 25ml. of water, 10.7 g. of 4-(3,4-dimethoxyphenyl) pyridine was added, andthe mixture heated at 8590 C. for one hour. The water was removed byheating on the steam bath under reduced pressure and the residue heatedunder reflux with 20 ml. of acetic anhydride for one hour. The excessanhydride was removed by distillation under reduced pressure and theresidue was dissolved in water. Benzene was added and the mixturebasified by the addition of solid potassium carbonate. The mixture wasfiltered and the solid washed with water and benzene. The filtrate wasseparated and the aqueous layer extracted once with benzene. The aqueouslayer was then extracted three times with chloroform and the filteredsolid was dissolved in the combined chloroform extracts. The solvent wasremoved and the residue recrystallised twice from benzene to give ayellow solid M.P. 1624 C.

This solid was dissolved in 20 ml. of ethanol saturated with hydrogenchloride and the solution was heated under reflux for one hour. Theethanol was removed and the residue recrystallised from a mixture ofmethanol and isopropanol to give 1-amino-4-(3,4-dimethoxyphenyl)pyridinium chloride as a yellow solid, M.P. 234-5 C.

EXAMPLE 6 Preparation of 1-amino-4-(3,4-dihydroxyphenyl) pyridiniumbromide 0.5 g. of the acetamido compound, M.P. l624 C., obtained as anintermediate in the preparation of l-amino- 4-(3,4-dimethoxyphenyl)pyridinium chloride was dissolved in a mixture of 1.5 ml. of glacialacetic acid and 1.5 ml. of 48% aqueous hydrogen bromide and the solutionwas heated under reflux for three hours. The solution was reduced todryness and the residue recrystallised from a mixture of methanol andisopropanol to give 1- amino-4-(3,4-dihydroxyphenyl) pyridinium bromideas a yellow/green solid, M.P. 2323 C.

EXAMPLE 7 Preparation of l-amino-2-phenylpyridinium chloride 2.1 g. ofZ-phenylpyridine was added to a freshly prepared solntion of 6.2 g. ofhydroxylamine-O-sulphonic acid in 50 ml. of water. The resultingsuspension was then heated on the steam bath for one hour, during whichtime most of the pyridine dissolved into the aqueous solution whichbecame yellow in colour. The initial efi'ervescence had ceased at theend of thirty minutes.

Water was removed at 40 C. under reduced pressure and the resultingyellow oil was heated under reflux with 100 ml. of acetic anhydride, forthree hours. Removal of the excess acetic anhydride under reducedpressure gave a brown oil which was then dissolved in 80 ml. of waterand basified with sodium carbonate. Extraction with benzene (3 x 50 ml.)removed unreacted Z-phenylpyridine.

The aqueous solution was extracted with chloroform (continuousextraction for two days). After drying over magnesium sulphate, thechloroform extract was evaporated to give a brown oil which began tosolidify on standing. This was dissolved in 100 ml. of methanolsaturated with dry hydrogen chloride and heated under reflux for twohours. Removal of volatile materials gave a brown oil which wasrecrystallised from ethanol/ethyl acetate (with charcoal) to givel-amino-Z-phenylpyridinium chloride as yellow crystals, M.P. l93-4 C.

EXAMPLE 8.-TABLETS Per tablet, For 4,000, g.

All the materials were sifted through a No. 60 BS. mesh sieve, mixedtogether thoroughly, then compressed to hard slugs of /2" diameter. Theslugs were reduced to granules by passing through a No. 16 BS. meshsieve, and finally compressed in a conventional tablet machine to givetablets each weighing 500 mg. and containing 100 mg. of the activeingredient.

In the above tablet, the amount of active ingredient may be variedWidely, and the chloride may be replaced by any other salt having apharmaceutically acceptable an1on.

Various well known pharmacologic procedures were carried out in dogs andcats to ascertain the anti-hypertensive activity of1-amino-4-phenylpyridinium chloride.

The control blood pressure and heart rate of renal hypertensive dogs wasdetermined, then l-amino-4-phenylpyridinium chloride was administereddaily for 10 consecutive days in a soft gelatin capsule, at a dose levelof 5 mg./kg. On the first day of the administration the compoundelicitated a large and sustained increase in blood pressure. Subsequentdaily administration did not cause a rise in blood pressure. The dogsshowed a decline in blood pressure of 30-60 mm. Hg range, with no changein heart rate, which reached a maximum after 2-3 days, and wasmaintained throughout the days of administration. The blood pressure ofthe dogs returned to pretreatment levels 3-6 days after withdrawal ofthe drug.

Experiments showed that the rise in blood pressure produced when1-amino-4-phenylpyridinium chloride was first administered could beavoided by the administration of small amounts of the drug in dailydivided doses, and then gradually increasing the dose level over severaldays until an antihypertensive response was obtained. The drug was givenorally at a dose level of 0.25 mg./kg. twice daily for 2 days to renalhypertensive dogs, then the dose level was raised to 0.5 mg./kg. twicedaily for 2 days, then to 1.0 rug/kg. twice daily for 7 days. Thisadministration did not elicit a rise in blood pressure. Doses of 0.5mg./ kg. lowered the blood pressure gradually over the 2 days ofadministration by approximately 30 mm. Hg. On increasing the dose levelto 1.0 mg./kg. twice daily, the blod pressure fell a further mm. Hg, butcontinued dosing did not maintain this fall. After 7 days the dose levelwas increased to 2 mg./kg. twice daily for 7 days, whereon the bloodpressure was again reduced and the fall was maintained. After withdrawalof the drug the blood pressure returned to near normal levels after 7-14days.

All dogs remained healthy during drug administration, and there were novisible signs of impaired sympathetic activity. In addition, no markedtolerance to the antihypertensive action of 1-amino-4-phenylpyridiniumchloride was observed when the drug was administered over a 10-dayperiod.

In anaesthetized dogs, the rise in blood pressure elicited by thebilateral occlusion of the common carotid arteries was consistentlyreduced by the intravenous administration of l-amino-4-phenylpyridiniumchloride at dose levels of 1 mg./kg. and above. The efiect was of longduration and the response did not usually recover before the experimentwas terminated (4-6 hrs.).

Acute studies were then carried out in anaesthetized cats. Theintravenous administration of 1-amino-4-phenylpyridinium chloride at adose level of 5 rug/kg. produced an initial rise followed by a fall inblood pressure. Larger doses, 10 mg./kg. produced a fall in bloodpressure of 40-60 mm. Hg for greater than 60 min.

What is claimed is:

1. A process for the preparation of a compound of the formulatrifiuoromethylphenyl, 3,4-dichlorotolyl, m-tolyl, phenyl ethyl orphenylpropyl and X- is a pharmaceutically acceptable anion, whichcomprises reacting a nitrosopiperidine derivative of the formula whereinR is as defined above, an acylating agent, to produce a pyridinederivative of the formula -N.Ae wherein Ac is acyl, and subjecting saidpyridine derivative to acid hydrolysis.

2. A process according to claim 1 wherein X is halide, acetate,bicarbonate, succinate, maleate, tartrate or methane-sulphonate.

3. A process according to claim 1 which comprises recovering thepyridinium salt produced.

References Cited Beckett et al.: Journal of Medicinal Pharmacology andChemistry, vol. 4, pp. 423-436 (1961).

Harper et al.: Journal of Medicinal Chemistry, vol. 10, pp. 819-823(1967).

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

